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WO1992005766A1 - Agents de lyse de bacteries orales - Google Patents

Agents de lyse de bacteries orales Download PDF

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Publication number
WO1992005766A1
WO1992005766A1 PCT/US1991/007310 US9107310W WO9205766A1 WO 1992005766 A1 WO1992005766 A1 WO 1992005766A1 US 9107310 W US9107310 W US 9107310W WO 9205766 A1 WO9205766 A1 WO 9205766A1
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Prior art keywords
formulation
concentration
humectant
recited
formulation recited
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English (en)
Inventor
Jerry J. Pollock
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Research Foundation of the State University of New York
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Research Foundation of the State University of New York
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/23—Sulfur; Selenium; Tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/463—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfuric acid derivatives, e.g. sodium lauryl sulfate

Definitions

  • the present invention relates to oral compositions, particularly dental rinses, dentifrices and the use of these oral compositions for effecting the lysis of oral bacteria.
  • a successful therapeutic composition for the treatment of oral disease should satisfy the following criteria:
  • composition should be readily available, without prescription to allow continuous daily treatment of the oral cavity.
  • the continued availability of the dentifrice preparation is needed since bacteria readily re-establish themselves in the absence of treatment.
  • Death of bacteria can be achieved either by bacteriocidal action (death without cellular lysis) or by a bacteriolytic action (death with lysis of the cell).
  • bacteriolysis leads to extensive cell wall and cell membrane damage followed by rupture of the bacterial cell and the release of cytoplasmic macro-molecular nucleic acid.
  • Agents that can elicit bacteriolysis are superior for the treatment of oral disease, because once lysed, the oral bacteria (which cause the oral disease) and their contents are completely washed off the oral surfaces (teeth, gums, tongue, cheek, etc.), swallowed and ultimately digested in the stomach where they are rendered harmless.
  • the network of bacteria that resides on the oral surfaces (the dental plaque) is completely disrupted since bacteriolysis results in the damage and loss of cell wall receptors responsible for both generalized interbacterial adherence and specific coaggregation between bacteria.
  • the dental plaque As surface layers of the dental plaque are shed, the deeper layers of the plaque now become accessible to the action of the bacteriolytic agent which results in further reduction of the amount of bacteria in the mouth.
  • levels of oral bacteria are sufficiently reduced, then the severity of oral diseases, such as dental caries, gingivitis, periodontitis and oral malodor is in turn reduced.
  • ingredients of the formulations may include benzethenium chloride, N-alkylpyridinium chloride, N-cetyl pyridinium bromide, sodium N-lauroyl sarcosine, N- dhyristoyle glycine and potassium N-lauroyl sarcosine.
  • the sodium salicylate or other analgesics comprise from about 0.1 to about 1% per weight of the rinse formulation.
  • the dental rinse described in the '750 and '708 patents is an alkaline solution having a pil of at least about 7.5 and above, but not greater than 10. it includes an oral surfactant and detergent builder in a liquid carrier.
  • the liquid carrier may include water or a solution of water and ethanol from about 70% to about 95% of the formulation.
  • Nonionic oral surfactants may include mixtures of laureate esters of sorbitol. and sorbitol anhydrides such as Tween 20.
  • oral surfactants include alkyl sulfonates or sul fates such as sodium lauryl sulfate or sodium N-lauryl snrcosinates in concentrations ranging from about 0.11 to about 101 by weight of the composition.
  • Detergent builders are also used such as sodium carbonate, sodium b ⁇ rate or alkaline mixtures of sodium carbonate and/or sodium borate with sodium bicarbonate in concentrations ranging from 0.11 to about 1% by weight of the dental rinse formulation. Additional adjuvant ingredients to provide desira ⁇ ie flavoring, coloring and mouth feel are included such as the flavorants thymol, eucalyptol or menthol and humectants such as glycerine in amounts up to about 201 which functions as a sweetener and imparts body to the composition. Equivalent materials such as sorbitol or propylene glycol may also be employed. A typical formulation is shown in examples 1 and 3 of the '708 patent.
  • Dreath freshener compositions including mints, candies, dental creams and mouthwashes are described in United States Patent Mo. 4,409,202.
  • the active ingredient in this patent is vegetable oil employed in combination with magnesium hydroxide.
  • Example 4 describes a mouthwash formulation which includes magnesium hydroxide and hydrated magnesium carbonate in combination with cottonseed oil, sodium bicarbonate in a concentration of 2.5 grams per 1,000 ml, and glycerine (a huiuectant) at a concentration of about 42% by weight (420 ml per 1,000 ml).
  • Oral surfactants and detergents are not inciuded in the mouthwash formulations (Examples 4 and 9).
  • a dental cream is described in Example 5, in which sodium lauryl sulfate is used in a concentration of about 1.5 parts by weight. It is important to note that the compositions of the '202 patent are not made for tlie purpose of effecting cell lysis or cell death of bacteria to destroy plaque, but rather for reducing mouth odor due to ingestion of onions and similar malodorous foods. This is especially evident since sucli dental creams are highly diluted during use by saliva and water. A germicide free antibacterial or mouthwasli composition is described in United States Patent No. 4,150,151.
  • the composition includes water, ethanol, flavoring such as spearmint or peppermint, and from about 0.1 to about 0.61 alkyl sulfate anionic surfactant mixture such as dodecyl and tetradecyl sulfate salt inciuding sodium lauryl sulfate, and nonionic emulsifiers may be included up to about 3% by weiglit.
  • a humectant may also be included in a concentration of up to about 25% by weight for the purpose of better mouthfeel.
  • compositions intended to cause cell lysis of oral bacteria may be up to 2% by weiglit of alkaline metal lialide, up to about 2% by weight of a buffering salt pair, up to about 2% of a sodium saccharin for a sweetening effect, and a make up quantity of water.
  • the '151 patent does not describe compositions intended to cause cell lysis of oral bacteria.
  • 2,689,170 describes an oral preparation for the inhibition of dental caries which includes a dental cream containing sodium lauryl sarcosides, calcium carbonate a flavorant and glycerine.
  • the glycerine or other humectant may range from about 5 to 50% by weight.
  • the dilution of the dentifrice formulation with water and saliva in the mouth is described in detail in column 5 of the patent.
  • a mouthwash formulation is described at column 17.
  • Humectants are not described in the compositions of the mouthwash formulation.
  • compositions having high humectant concentrations needed for preventing hardening, such as glycerine or sorbitol at a level from about 15 to about 70% by weight are described in U.S. Patent No. 4,846,650.
  • the compositions include an anticalculus agent, polyepoxysuccinic acid and its pharmaceutically- acceptable salts.
  • Emulsifying agents such as sodium alkyl sulfate, are also used in this formulation .
  • humectants are used in much lower concentrations of up to about 20%, preferably up to about 5% by weight. The humectants are not used in this formulation for anything other than their moistening and mouthfeel properties.
  • a feature of the present invention is to provide a composition and method for the treatment of gingivitis and periodontal disease which removes dental plaque and prevents new plaque build up.
  • Another aspect of the present invention is to provide a composition which causes lysis and cell death of oral bacteria which constitutes and is imbedded in dental plaque.
  • a further feature of the present invention is to provide a composition which rapidly lyses and kills oral bacteria over a very short periods of exposure.
  • compositions of the present invention include a humectant such as glycerol, sorbitol or comparable compounds and provide an in-mouth concentration of such substances from about 20% to about 80% weight/volume in dentifrice preparations, in particular mouthrinses.
  • humectant such as glycerol, sorbitol or comparable compounds
  • These compositions further comprise (a) bicarbonate ion at about 0.5% to about 2% wt./vol. and if desired, thiocyanate, chloride or fluoride ion at about 0.5% to about 2% wt./vol.
  • alcohol may be added up to a level of 15% vol./vol. along with appropriate sweetening and flavoring agents. Water is then added to 100%.
  • compositions may be introduced in a manner and vehicle suitable for oral cavity administration.
  • This invention also relates to a method of using such compositions for treating and inhibiting dental caries, dental plaque and gingivitis, oral malodor and periodontopathic conditions in mammals, particularly humans, in need of anti-caries, anti-plaque, anti- gingivitis, anti-malodor or anti-periodontopathic therapy.
  • the compositions of the present invention are conventionally formulated into mouthrinses (mouth washes) and the commonly utilized dentifrice treatment agents, that is, dental creams, toothpastes and toothp ⁇ wders, as well as into typically chewed carriers such as gums, lozenges and candies.
  • Figure 1 is a graph illustrating the effect of glycerin and antibacterial agents on cell lysis (bacteriolytic activity) of the bacterium Lactobacillus casei DSM.
  • Figure 2 is a graph illustrating the effect of glycerin containing mouthrinses on cell lysis of the bacterium Streptococcus sanguis 10557.
  • Figure 3 is a graph illustrating the effect of sodium lauryl sulfate on cell lysis of Streptococcus mitis 905.
  • Figure 4 illustrates the effect of mouthrinses on cell lysis of Actinomyces naeslundii.
  • Figure 5 illustrates the effect of Tween 20 concentrations on cell lysis of Antinomyces viscosus.
  • Figure 6 is a graph showing a typical example of cell lysis of a gram-negative plaque bacterium, Haemophilus parainfluenza, by the preferred bacteriolytic mouthrinse of the present invention.
  • Figure 7 is a graph illustrating cell lysis of a gram-negative periodontopathic odor causing bacterium, Fusobacterium nucleatum by bicarbonate and the preferred bacteriolytic mouthrinse of the present invention.
  • Figure 8 is a graph illustrating the cell lysis of a gram-negative periodontopathic bacterium, Actinobacillus actinomycetemcomitans by bicarbonate and by the preferred bacteriolytic mouthrinse composition of the present invention.
  • compositions adapted for the lysis of oral bacteria are provided.
  • anticariogenic for example, lysis of Streptococcus mutans and Lactobacillus casei
  • antiplaque-antigingivitis for example, lysis of Streptococcus sanquis types I and II, Streptococcus mitis, Staphylococcus epidermidis, Actinomyces viscosus, Actinomvces naeslundii, Haemophilus parainfluenza, Neisseria sicca, Veillonella dispar and Fusobacterium nucleatum
  • antimalodor primarily, Fusobacterium nucleatum and Bacteriodes gingivalis
  • antiperiodontopathic for example lysis of Fusobacterium nucleatum, Capnocytophaga gingivalis, Bacteroides gingivalis, Actinobacillus actinomycetemcomitans and Eikenella corroden
  • compositions of the present invention include a humectant such as glycerol, sorbitol or comparable compounds and provide an in-mouth concentration of such substances from about 20% to about 80% weight/volume in dentifrice preparations, in particular mouthrinses.
  • humectant such as glycerol, sorbitol or comparable compounds
  • These compositions further comprise (a) bicarbonate ion at about 0.5% to about 2% wt./vol. and if desired, thiocyanate, chloride or fluoride ion at about 0.5% to about 2% wt./vol.
  • sodium lauryl sarcosinate or other anionic detergents from about 0.05% to about 1% wt./vol.
  • compositions may be introduced in a manner and vehicle suitable for oral cavity administration.
  • This invention also relates to a method of using such compositions for treating and inhibiting dental caries, dental plaque and gingivitis, oral mal ⁇ dor and periodontopathic conditions in mammals, particularly humans, in need of anti-caries, anti-plaque, anti- gingivitis, anti-malodor or anti-periodontopathic therapy.
  • compositions of tlie present invention are conventionally formulated into mouthrinses (mouth washes) and the commonly utilized dentifrice treatment agents, that is, dental creams, toothpastes and toothpowders, as well as into typically chewed carriers such as gums, lozenges and candies.
  • the preferred embodiment of the present invention is an oral rinse having agents which cause lysis of oral bacteria.
  • the oral rinse may be used for the lysis of a broad spectrum of bacteria in the mouth, used either as a mouthwash or dispensed in a device such as WATERPIK ® below the gingival margin.
  • Tlie mouthwash also contains bicarbonate ions from about 0.5% to about 2% wt./vol. and optionally thiocyanate, chloride or fluoride ions as an anti-caries ingredient from about 0.5% to about 2% wt./vol.
  • An anionic detergent is also required such as sodium lauryl sarcosinate or other anionic detergents such as sodium lauryl sulfate in the range of from about 0.05% to about 1% wt./vol. preferably about 0.41 wt./vol.; and non-ionic detergents or structurally similar compounds sucli as Tween 20 in a range of from about 0.011 to about 3% vol./vol., preferably about 1% vol./vol.
  • Other in ⁇ redients could include alcohol at about no to 15% vol./vol., appropriate sweetening and flavoring agents and water added to make up tlie remaining 100%.
  • autolysins located at tlie juncture of tlie cell membrane and cell wall became suceptibie to deregulation by activating agents such as inorganic monovalent anions or detergents, and are probably activated.
  • the autolysins hydrolyze chemical bonds in the cell wall and produce holes in the bacterial cell membranes. Normally, these autolysins are important to the bacteria for growth and division, but once deregulated and activated they cause bacterial suicide.
  • tlie mouthwash composition i.e. bicarbonate
  • lytic facilitation in tlie mouthwash composition (i.e. bicarbonate)
  • saliva causes massive cell lysis and cell death.
  • massive lysis and death of bacteria constituting plaque leads to the destruction and elimination of the plaque.
  • bacteria are bathed by saliva and salivary lysing agents (lysozymes) which interact with and damage the bacteria.
  • salivary lysing agents lysozymes
  • Tlie bacteria swelled by the humectants and damaged by saliva allow penetration of bicarbonate and detergents into the cell, deregulating and activating the bacterial autolysins.
  • humectants do not cause bacterial lysis, rather the bacteria seem to remain alive and even grow if lytic activating agents such as Tween, bicarbonate and sodium lauryl sarcosinate have not been included.
  • compositions of the present invention facilitate maximal lysis of oral bacteria by using an in- mouth concentration (i.e. 20-001 wt./vol.) of the humectant (e.g., glycols, sugar alcohols, corn syrup, etc.) in dentifrice preparations.
  • humectants normaly provide body and consistency to the formulation and also a smooth, pleasant feel upon swirling or brushing in the mouth.
  • tlie level of tlie humectant for example, glycer ⁇ l or sorbitol alone is not e h to effect lysis of the bacteria, rather, this key ingredient facilitrites lysis upon addition of other agents, such as, inorganic monovalent anions (for example, bicarbonate and thiocyanate), anionic surfactant detergents (for example sodium lauryl sulfate or sodium lauryl sarcosinate) or non-ionic surfactant detergents (for example, Tweens or polymers of polyoxyethylene and polyprppylene).
  • inorganic monovalent anions for example, bicarbonate and thiocyanate
  • anionic surfactant detergents for example sodium lauryl sulfate or sodium lauryl sarcosinate
  • non-ionic surfactant detergents for example, Tweens or polymers of polyoxyethylene and polyprppylene.
  • the highly effective lytic compositions of the present invention also cause deregulation of the autolysins and lysis of the cell directly, even in the absence of prior lysozyme damage.
  • These new compositions therefore, allow maximal lysis and provide a distinct advantage, in that to facilitate lysis tlie dental plaque does not have to be covered by salivary lysozyme and salivary proteases, which may in fact be present in saliva, albeit in limited concentrations.
  • the superior bacteriolytic properties of the preferred compositions of tlie present invention were demonstrated by both standardized in vitro assay procedures involving both the cell lysis and cell death of the bacteria and also by in vivo human clinical studies.
  • the lysis was assayed by spectrophotometric reductions in turbidity of bacterial cell suspensions (illustrated in Figs. 1-8) and cell death was measured by the number of surviving bacterial colony forming units compared to untreated controls plated onto appropriate agar media (shown in Tables 1-10).
  • Tlie oral bacteria used in these examples were either isolated from lesion sites in the mouth or were purchased from the American Type Culture Collection (Rockville, Maryland).
  • Bacteria were grown from lyophilized cultures in their respective bacteriological media to the late log phase of growth. After transfer to fresh media, growth was allowed to proceed to late log phase. Bacterial cells were harvested and washed once in distilled water. During the bacterial harvesting and washing procedure, whole saliva (50 to 70 milliliters) was collected by stimulation with paraffin wax. The saliva was adjusted to pil 4.5 to stabilize tlie lysozyme activity and was left on ice for 20 minutes. Tlie saliva was centrifuged to yield the salivary supernatant which was adjusted to pil 5.3 for lytic assays of gram-positive bacteria and also to pil 7.0 for gram-negative bacteria.
  • Pelleted bacteria were suspen in the salivary supernatant for a period of 90 minutes (for gram-positive bacteria) and 30 minutes (for gram-negative bacteria). After the incubation period, salivary suspensions were distributed into 2.5 ml aliquots in screw cap tubes and centrifugation was carried out. Cell pellets were then rapidly resuspended in tlie various mouthrinses and optical densities (turbidities) at 675 nm were immediately measured and followed for a period of up to 1 hour incubation at 37°C. In the first minute, aliquots of 100 micr ⁇ liters of each mouthrinse suspension were removed and diluted into 900 ul of bacteriological media (10 -1 dilution).
  • Lysis was confirmed by radioactive thymidine assays according to methodologies described in U.S. Patent Nos. 4,610,409 and 4,061,502, tlie disclosure of both patents are incorporated by reference herein. Lysis was also measured in the absence of saliva treatment; that is, distilled water replaced the 30 minute or 90 minute treatment of the freshly grown bacteria, prior to either the water control or mouthrinse treatment.
  • Lactobacilli which are also cariogenic bacteria
  • Lactobacillus plantarum is easily lysed by inorganic monovalent anions; however, Lactobacillus casei, for reasons unknown, is not lysed to any great extent in the presence of saliva.
  • Figure 1 is a graph illustrating the effect of varying glycerin concentrations with and without antibacterial agents on cell lysis of Lactobacillus casei DSM.
  • the line having the lowest optical density is x, illustrating a preferred mouthrinse formulation (Test Agent #5) containing 40% glycerin (or sorbitol) + 3% Tween 20 + 7.5% ethanol + 1.5% sodium bicarbonate + 0.5% sodium thiocyanate.
  • Figure 1 shows that the combination of sodium bicarbonate and sodium thi ocyanate has some effect on reducing the optical density (decreasing the turbidity in effect to lyse the cell) of Lactobacillus casei in agreement with earlier findings.
  • lysis and cell death of L. casei cells can be accomplished by adding glycerol or sorbitol in the presence of lytic activating agents (see Test Agent # 4 ,
  • Table 1 The data in Figure 1 and Table 1 suggest that the inorganic monovalent anions (bicarbonate and thiocyanate) are one type of lytic activator; however, the complete killing of the L. casei bacteria within one minute by a mouthrinse containing 40% glycerin or 40% sorbitol (Table 1) with the additional. ingredients suggests that agents other than the inorganic monovalent anions, are lytic activators.
  • Figure 1 also demonstrates that the mouthrinse containing 40% glycerin or sorbitol is significantly more effective in promoting cell lysis (larger drop in optical density or turbidity) than a mouthrinse containing only 20% glycerin or sorbitol.
  • a comparison of the killing activity of the two mouthrinses further indicates tliat the 40% humectant concentration is superior to the 20% concentration of humectant, as there are still surviving L. casei microbes with the lesser concentration (Table 1).
  • Figure 2 shows the effect of glycerin containing mouthrinses at varying glycerine concentrations on cell lysis of Streptococcus sanquis 10557.
  • a preferred formulation (Test Agent #11, Table 2 ) contained 40% glycerin + 3% Tween 20 + 1.5% ethanol + 1.5% sodium bicarbonate + 0.5% sodium thiocyanate + 0.5% sodium lauryl sulfate produced the most dramatic results.
  • Test Agent #11, Table 2 40% glycerin + inorganic monovalent anions + Tween 20 + other ingredients, is far superior in causing cell death.
  • the latter findings with the preferred formulation suggests that still another type of agent is important in the cell death process.
  • Figure 2 shows that Test
  • Agent #11 is more effective in lysing or reducing the optical density of S. sanguis than Test Agent #10 or Test
  • Agent #9 (40% glycerin alone) or Test Agent #12 (20% glycerin mouthrinse). Noteworthy, the 20% glycerin mouthrinse (Test Agent #12) is significantly less effective than the preferred 40% glycerin mouthrinse,
  • Figure 3 and Table 3 show the effect of sodium lauryl sulfate on cell lysis and cell death of Streptococcus mitis 905. As shown in Figure 3 and Table 3, the most dramatic results are observed in using a preferred composition containing 40% glycerin 3% Tween 20 + 7.5% ethanol + 1.5% sodium bicarbonate + 0.5% sodium thiocyanate + 0.5% sodium lauryl sulfate.
  • Figure 3 shows that the third type of lytic activating agent for use in the preferred composition is an anionic surfactant, for example, sodium lauryl sulfate which, when added to the mouthrinse, further enhances the cell lysis of Streptococcus mitis.
  • Table 3 confirms that the addition of sodium lauryl sulfate to the mouthrinse (compare preferred Test Agent #4 with Test Agent #3) significantly enhances the killing of this bacterium. Although this anion surfactant alone is effective in killing S. mitis (see composition #2, Table 3), Figure 3 shows that the sodium lauryl sulfate by itself does not decrease turbidity of the cell suspension, and therefore does not promote cell lysis unless present with a lytic facilitator.
  • Figure 4 and Table 4 illustrate that combinations of 40% glycerin + 3% Tween 20 + 0.5% sodium lauryl sulfate are not as effective in either maximally lysing or killing of Actinomvces naeslundii 19039 as when these ingredients are present together along with inorganic monovalent anions (preferred composition #4, Table 4).
  • the data also suggests that although sodium lauryl sulfate is an effective killing agent (see Table 4), it by itself does not decrease turbidity of the cell culture, and therefore does not promote cell lysis unless present with a lytic facilitator.
  • Figure 5 shows the effect of various Tween 20 concentrations in the preferred conposition of the present invention on cell lysis of Actinomyces viscosus 19246, and compares those effects with those obtained using a commercially available mouthrinse PLAX. The most dramatic effects are for preferred composition (Test Agent #4) containing 40% glycerin + 1% Tween 20 + 7.5% ethanol + 1.5% sodium bicarbonate + 0.5% sodium thiocyanate + 1% sodium lauryl sulfate.
  • Figure 5 and Table 5 show that Tween 20 displays a concentration dependence for both bacteriolysis (Fig. 5) and cell death (Table 5) of Actinomvces viscosus.
  • PLAX Teest Agent #5, Fig. 5
  • PLAX Steer Agent #5
  • PLAX Steer Agent #5
  • U.S. Potent Nos.4,666,708 and 4,657,758 PLAX is shown to be significantly less effective in lysing and killing this major plaque species (Table 5) as well as other microbes (data not shown) when compared to the mouthrinses of the present invention.
  • Example 6 compares the effect of variations in the concentration of ionic detergents in mouthrinses made in accordance with the present invention.
  • LJasic mouthrinse 1 contains 40% glycerol + 3% Tween 20 + 7.5% ethanol + 1.5% sodium bicarbonate + 0.5% sodium thiocyanate.
  • Basic mouthrinse II contains 30% sorbitol + 1% Tween 20 + 7.5% ethanol + 1.5% sodium bicarbonate + 0.5% sodium thiocyanate.
  • tlie level of cell death of this microbe is also dependent on tlie anionic detergent concentration (compare Test Agent # 2 with #3 or Test Agents #4 , 5, 6, 7, 0, 9 to each other).
  • Table 6 also shows that sorbitol is more effective than glycerol (compare Test Agents #2 and 3 with Test Agent # 10) in promoting cell death, although botli appear equally effective in promoting cell lysis.
  • sodium lauryl sarcosinate an anionic surfactant detergent, appears to be equally effective as sodium lauryl sulfate.
  • the sarcosinate salt is preferred over the sulfate, since the sarcosinate permits greater stability at lower temperatures with less oral toxicity.
  • Table 7 shows the effect of variations in pll of the mouthrinse of the present invention on cell death of Actinomvces viscosus 15907. As shown in Tabie 7 , cell death is also dependent on pll. Although higher antimicrobial activity is seen at pll 6 (Iauryl sarcosine acid form), the stability of lauryl sarcosinate is known to be better at alkaline pll. The formulations could therefore be used within a broad pll range.
  • Example 8 Figure 6 illustrates that tlie mouthrinse combination is effective in lysing typical gram-negative dental plaque microbes sucli as Ilaemophilus parainfluenza.
  • Figure 7 and Table 8 show tlie effects of two preferred mouthrinse compositions of the present invention on gramnegative periodontopathic odor causing bacterium Fusobacterium nucleatum.
  • both preferred mouthrinses can both maximally lyse Fusobacterium nucleatum, a gram-negative bacterium implicated in oral malodor, gingivitis and periodontal disease.
  • Lysis of Fusobacterium nucleatum is extremely rapid so that within the first minute of testing, 100 percent of the cells are destroyed by the mouthrinse (see Table 8). The same is true for Dacteriodes qinqivolis (data not shown) and for Acinomyces actinomycetemcomitans (shown in Figure 8 and Table 9), a pathogen involved in causing juvenile periodontitis.
  • Radioactive thymidine experiments further show that the preferred combination of lytic facilitator and lytic activating agent in tlie mouthrinses of the present invention (for example, Test Agents #3 and #4, described in Example 4 at Table 4 ) cause true lysis of all of the above described bacteria by effecting release of macromolecular DNA from the interior of tlie cell. The latter can only be accounted for by extensive damage due to explosion of the cell wall and cell membrane (also seen by electron microscopy) making holes large enough in the cell membrane and cell wall for the DNA to escape.
  • lytic facilitator and lytic activating agent in tlie mouthrinses of the present invention for example, Test Agents #3 and #4, described in Example 4 at Table 4
  • Table 10 Components of the Preferred Dental Moutlirinse formulation of Example 10, based on a total volume of 100 ml.
  • the six teeth chosen were the Ramfjord teeth which include the maxillary right first molar, the maxillary left central incisor, the maxillary left first premolar, the mandibular left first molar, the mandibular right central incisor and the mandibular right first premolar.
  • the amount of dental plaque on the teeth was also visualized with the use of disclosing tablets after which a series of intraoral photographs were taken of different areas of each patient's mouth. Gingival index was scored according to the Loe and Silness Index (Journal of Periodontology 36:178, 1965) along the gingival margin of the six Ramfjord teeth using the following scheme:
  • Table 12 Components of the preferred mint flavored dental mouthrinse formulation of Example 11, based on a total volume of 100 ml.
  • the lytic formulation could easily be incorporated into different dentifrice preparations and other formulations described in Examples 12-18:
  • the formulation is utilised by rinsing the mouth for about 30 to 60 seconds from 1-3 times per day with about 15 ml of undiluted mouthwash.
  • Example 15 The formulation is utilized by cleaning the teeth with about 1 to 2 gm of paste between 1 to 3 times per day.
  • Example 15 The formulation is utilized by cleaning the teeth with about 1 to 2 gm of paste between 1 to 3 times per day.
  • the formulation is utilized by cleaning the teeth with about 1 to 2 gm of paste between 1 to 3 times per day,
  • Tlie formulation is utilized as needed.
  • the formulation is utilized as needed.
  • the formulation is utilized as needed.

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  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Cosmetics (AREA)

Abstract

L'invention concerne une composition utilisée pour lyser et tuer des microbes en général et notamment des compositions orales utilisées pour lyser et tuer des bactéries orales. La composition de l'invention comprend un humectant tel que le glycérol, le sorbitol ou des composés comparables et elle se caractérise par une concentration à l'intérieur de la bouche desdites substances comprise entre environ 20 % et environ 80 % en poids/volume dans des préparations de dentifrice, notamment des bains de bouche. Ces compositions comprennent également (a) un ion bicarbonate représentant environ 0,5 à environ 2 % en poids/vol et si désiré un ion thiocyanate, chlorure ou fluorure représentant environ 0,5 à environ 2 % en poids/vol, (b) du sodium lauryl sarcosinate ou d'autres détergents anioniques représentant environ 0,05 à environ 1 % en poids/vol, et (c) Tween 20 ou d'autres détergents non ionisants, ou bien des composés structurellement similaires représentant environ 0,01 à environ 3 % en vol/vol. De plus, on peut additionner de l'alcool jusqu'à un niveau de 15 % en vol/vol ainsi qu'un agent édulcorant ou aromatisant approprié. On ajoute ensuite de l'eau pour atteindre 100 %.
PCT/US1991/007310 1990-10-04 1991-10-04 Agents de lyse de bacteries orales Ceased WO1992005766A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/592,552 US5185153A (en) 1990-10-04 1990-10-04 Agents effecting the lysis of oral bacteria
US592,552 1990-10-04

Publications (1)

Publication Number Publication Date
WO1992005766A1 true WO1992005766A1 (fr) 1992-04-16

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US (1) US5185153A (fr)
AU (1) AU8744491A (fr)
WO (1) WO1992005766A1 (fr)

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WO2018194948A1 (fr) * 2017-04-19 2018-10-25 Wm. Wrigley Jr. Company Synergie d'extrait de réglisse avec du menthol dans un produit de confiserie, pour rafraîchissement d'haleine
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US5185153A (en) 1993-02-09

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